Vitamin D receptor activation reduces hepatic inflammation via enhancing macrophage autophagy in cholestatic mice

Am J Pathol. 2023 Dec 15:S0002-9440(23)00462-5. doi: 10.1016/j.ajpath.2023.11.016. Online ahead of print.ABSTRACTMacrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. Here, to determine whether the vitamin D (VD)/ VD receptor (VDR) axis could upregulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL, VDR agonist) was intraperitoneally injected into bile duct ligated (BDL) mice for 5 days. Research found that upregulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress (OS)-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide (tBHP) treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD and the ROS scavenger NAC blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, upregulation of VDR also appeared to enhance macrophage autophagy. Autophagy reduction impaired the upregulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38MAPK pathway. This result was confirmed by p38MAPK inhibitor, MAPK activator and ROS inh...
Source: Am J Pathol - Category: Pathology Authors: Source Type: research